It is proposed to study the roles of cyclic AMP-dependent, cyclic GMP-dependent, and calcium-dependent protein kineases and their substrates in normal and abnormal brain function and in the mechanism of action of antipsychotic drugs. The specific program to be undertaken involves studies in several areas: (1) to search possible regulation by neurotransmitters and psychoactive drugs of the sate of phosphorylation of protein kinase substrates in slices prepared from various brain regions; (2) to prepare pure cyclic AMP-, cyclic GMP-, and calcium-dependent protein kinases, and their endogenous substrates; (3) to prepare antibodies to the protein kinases and their substrates, to develop radioimmunoassay procedures for the protein kinases and their substrates using these antibodies, and to determine the amount of the protein kinases and their substrates present (a) in various regions of the brain, (b) at various times during development of the brain, (c) after chronic treatment with various psychoactive drugs, and (d) in brain samples from normal and mentally-ill human subjects, using these radioimmunoassay procedures; (4) to identify, purify and characterize the phosphoprotein phosphatases for the endogenous protein kinase substrates in brain; and (5) to develop procedures for measuring the amount of mRNA for the endogenous substrates and to study the effects of various physiological and pharmacological manipulations on the amount and rate of transcription of the mRNA for these substrates.